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Lipopolysaccharide (LPS) and tissue factor (TF) have frequently been used to induce disseminated intravascular coagulation (DIC) in experimental animal models. We have previously reported that the pathophysiology of DIC differs according to the inducing agents. However, inflammatory status and bleeding symptoms have not been fully compared between rat models of the two forms of DIC. We attempted to evaluate detailed characteristic features of LPS- and TF-induced DIC models, especially in regard to inflammatory status and bleeding symptoms, in addition to selected hemostatic parameters and pathologic findings in the kidneys. The degree of hemostatic activation in both types of experimental DIC was identical, based on the results of thrombin-antithrombin complex levels. Markedly elevated tumor necrosis factor, interleukin-6, and high-mobility group box-1 concentrations were observed with severe organ dysfunction and marked fibrin deposition in the kidney on administration of LPS, whereas markedly elevated d-dimer concentration and bleeding symptoms were observed with TF administration. Pathophysiology such as fibrinolytic activity, organ dysfunction, inflammation status, and bleeding symptom differed markedly between LPS- and TF-induced DIC models in rats. We, therefore, recommend that these disease models be assessed carefully as distinct entities to determine the implications of their experimental and clinical use.

Tranexamic acid (TXA) is widely used as a hemostatic agent and for various other indications, including dermatological and inflammatory conditions. However, its association with thromboembolism in the real-world setting remains unclear. In this study, we aimed to evaluate this association. We collected data from the Japan Adverse Drug Event Report database from Q1 2004 to Q3 2020 and performed reporting odds ratio analyses and multivariate logistic regression analysis. Overall, 1,735,923 reports were analyzed. TXA was the suspected causal drug in 54 cases of venous thromboembolism (VTE) and 8 cases of arterial thromboembolism. A significant signal was detected for VTE (reporting odds ratio=6.61; 95% confidence interval=5.03-8.70) but not for arterial thromboembolism. VTE cases involving TXA were more frequently reported in women and individuals with a body mass index of ≥25 than in other groups. TXA may be associated with VTE. The findings highlight the importance of careful patient monitoring during TXA administration, particularly in high-risk populations such as women and individuals who are overweight.

Background: In Japan, the involvement of hospital pharmacists in inappropriate medications (IMs) practices has not been sufficiently reported. Therefore, this prospective study described the interventions of hospital pharmacists in discontinuing inappropriate drugs or reducing drug doses. Methods: We conducted a prospective, multicenter, observational study to investigate the intervention of hospital pharmacists in inappropriate prescriptions for inpatients in September 2018. Fifty pharmacists from 45 hospitals in Japan participated in this study. IMs were defined as medications that pharmacists deemed inappropriate for patient treatment. The subjects of the study were patients who interacted with the participating pharmacists. Results: During the study period, the median number of beds in hospitals where the 50 participating pharmacists worked was 380, and the average number of beds for which the pharmacists were responsible was 49. The enrolled hospital pharmacists recommended that doctors discontinue or reduce the doses of their regular drugs for 347 out of 1,415 (24.5%) patients. Among the 391 pharmacists’ recommendations to reduce IMs for 347 patients, physicians accepted 368 (94.1%) recommendations, and 523 drugs were discontinued as a result. Pharmacist intervention also led to improvements in hypnotic sedation, delirium, and hypotension. The most common reasons for IMs identified by pharmacists were “long-term administration of irresponsible or aimless medications” (44.5%), “adverse effects caused by medications” (31.5%), and “medications-mediated duplication of the pharmacological effect” (15.3%). Approximately 90% of pharmacists’ suggestions to reduce medications were accepted for each reason. The average number of regular medications used by patients involved in drug reduction was 8.2, and the average number of medications reduced was 1.7. A sub-analysis showed that patients using opioids tended to take more medications, and these patients were able to reduce the amount of medications taken. Interventions by pharmacists certified in palliative pharmacies tended to reduce adverse drug events. Conclusion: This was the first multicenter prospective observational study conducted in Japan to demonstrate hospital pharmacist intervention’s effectiveness in promoting appropriate prescription and, consequently, a reduction in the number of medications in use and polypharmacy.

Background Hyposalivation is treated using oral cholinergic drugs; however, systemic side effects occasionally lead to discontinuation of treatment. We aimed to investigate the effects of transdermal pilocarpine on the salivary gland skin on saliva secretion and safety in rats. Methods Pilocarpine was administered to rats orally (0.5 mg/kg) or topically on the salivary gland skin (5 mg/body). Saliva volume, the number of sweat dots, and fecal weight were measured along with pilocarpine concentration in plasma and submandibular gland tissues. Results Saliva volume significantly increased 0.5 h after oral administration and 0.5, 3, and 12 h after topical administration. Fecal weight and sweat dots increased significantly 1 h after oral administration; however, no changes were observed after topical application. The pilocarpine concentration in the submandibular gland tissues of the topical group was higher than that in the oral group at 0.5, 3, and 12 h of administration. Conclusions Pilocarpine application to salivary gland skin persistently increased salivary volume in rats without inducing sweating or diarrhea. Transdermal pilocarpine applied to the skin over the salivary glands may be an effective and safe treatment option for hyposalivation.

Background/Aim: We examined the mechanism of nitric oxide (NO) production in a tissue-factor (TF)-induced disseminated intravascular coagulation (DIC) model in rats, using inducible nitric oxide synthase (iNOS) inhibitor (L-NIL), endothelial nitric oxide synthase (eNOS) inhibitor (L-NAME), Factor Xa inhibitor (DX-9065a), and thrombin inhibitor argatroban. Materials and Methods: Experimental DIC was induced by sustained infusion of 3.75 U/kg TF for 4 h via the tail vein. We then investigated the effect of these four agents on TF-induced DIC. Results: Administration of L-NIL or L-NAME during induction of TF-induced DIC did not affect hemostatic markers, whereas elevated plasma levels of NO metabolites (NOX) were significantly suppressed by co-administration of L-NAME. A significant increase in eNOS-mRNA expression was observed in the TF-induced DIC model. Argatroban almost completely suppressed eNOS-mRNA expression. Conclusion: eNOS plays an important role in the NO production in the TF-induced DIC, and thrombin is a key stimulant of eNOS-mRNA expression in this model.

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain ( SLC2A1 , SLC2A3 , and SLC23A2 ) on APOE4-associated risk of developing cognitive decline. This case–control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2 , and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05–3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05–5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58–6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.

Background: The tolerability of 2-weekly docetaxel at 25-35 mg/m2 for castration-resistant prostate cancer (CRPC) has not been fully evaluated. The aim of this study was to evaluate its tolerability compared to 3-weekly docetaxel at 60-75 mg/m2 in patients with CRPC. Patients and Methods: In this retrospective study, data were compared with respect to efficacy and safety between 2-weekly and 3-weekly docetaxel regimens in patients with CRPC. Results: Time to treatment failure and prostate-specific antigen (PSA) response rate did not differ significantly between the two regimens. Compared to 3-weekly administration, incidence of severe leukopenia and febrile neutropenia was significantly lower (p<0.05), and relative dose intensity was significantly higher (p<0.05) for the 2-weekly schedule. Docetaxel dosage and PSA response were identified as independent risk factors for severe leukopenia. Conclusion: Two-weekly treatment seems better tolerated than three-weekly treatment in Japanese patients with CRPC.

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated risk of developing cognitive decline. This case–control study involved 393 Japanese subjects: 252 cognitively normal and 141 cognitively impaired individuals (87 mild cognitive impairment and 54 dementia). Database searches revealed that rs1279683 of SLC23A2, and rs710218 and rs841851 of SLC2A1 are functional variants that are significantly associated with the altered expression of the respective genes and genotyped as three single nucleotide variants (SNVs). When stratified by SNV genotype, we found a significant association between APOE4 and cognitive decline in minor allele carriers of rs1279683 (odds ratio [OR] 2.02, 95% CI, 1.05–3.87, p = 0.035) but not in the homozygote carriers of the major allele. Significant associations between APOE4 and cognitive decline were also observed in participants with major allele homozygotes of rs710218 (OR 2.35, 95% CI, 1.05–5.23, p = 0.037) and rs841851 (OR 3.2, 95% CI, 1.58–6.46, p = 0.0012), but not in minor allele carriers of the respective SNVs. In contrast, the three functional SNVs showed no significant effect on cognitive decline. Our results imply that functional SNVs of VC transporter genes can affect APOE4-associated risk of developing cognitive decline via altered VC levels in the brain.

The aim of the present study was to clarify the effect of recombinant human erythropoietin (EPO) and low molecular weight heparin (LMWH) on a rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC). Experimental DIC was induced by sustained infusion of 5 mg/kg LPS for 4 h. EPO or LMWH was then administered to the LPS-induced DIC model. LPS-induced consumption coagulopathy, hemostatic activation and plasma TNF elevation remained unaltered in the LPS+EPO group, except for the D-dimer levels, and these abnormalities were significantly improved in the LPS+LMWH group. Plasma alanine aminotransferase (ALT) levels were markedly reduced in the LPS+EPO group, accompanied by a significant suppression of hepatocellular apoptosis. In the LPS+LMWH group, plasma creatinine levels and glomerular fibrin deposition were significantly attenuated, along with plasma ALT levels and hepatocellular apoptosis. Thus, a single administration of EPO may improve hepatic dysfunction by primarily exerting an anti-apoptotic, not anticoagulant, effect in the LPS-induced DIC model.